Absorption
After you inject insulin, it goes into the bloodstream to workMerck Veterinary Manual-Disposition & Fate of Drugs. If the insulin is R/neutral or one of the non-mixed analogs, it will be absorbed quickly. Fast-acting insulins are designed to be absorbed even faster, while insulin suspensions are made to "hinder" the rapid absorption of the insulin, to make them work for a longer time period. The importance of how insulin is absorbed after it is injected under the skin is illustrated in this 2002 ADA Diabetes Care study, where Short-acting R/Neutral and Long-acting Lantus were compared when given intravenously, as opposed to subcutaneous use. Researchers found nothing slow-acting about Lantus when it was given intravenously, and they concluded that it is the absorption process from beneath the skin which produces the quite different effects these two haveIntravenous Glargine (Lantus) & Regular (Neutral) Insulin Similar Effects on Endogenous Glucose Output & Peripheral Activation/Deactivation Kinetic Profiles-ADA-Diabetes Care-2002. Absorption varies from patient to patient; this is why some patients get more or less duration from an insulin than another patient using the same thingDiabetes Forecast-ADA, 2006-Page 2. It also can vary for the individual patient from day to dayMerck Veterinary Manual-Disposition & Fate of Drugs. Absorption is one of the factors in insulin variabilityDiabetes-World Mailing List Web Site-Questions About InsulinInsulin Treatment-Individual Factors. Neutral Neutral or R insulin is basically zinc insulin crystals dissolved in clear fluid with nothing added to alter its action or speedUS FDA-Humulin R. This is true regardless of the insulin's species of origin; it has a normal absorption profile. Insulin molecules clump together naturally into "hexamers" (groups of six), which then drift apart when sufficiently diluted. The clumped form of hexamers, cannot be used directly, so there's a bit of time delay using R insulin while they are broken down into dimers and monomers. It might be easier to visualize this by thinking of a whole pie, slicing it into 6 pieces and putting one slice each on separate plates. The pie can't be eaten until it has been cut and served on plates. A normally working pancreas secretes insulin in monomer form, so there's no formation of hexamers by self-association and nothing to break down; the monomer insulin is ready to workChemistry and Pharmacology of Therapeutic Insulin Preparations, Abrams-Ogg, ACVIM 2007. Faster-acting It is possible to "speed" the absorption of insulin; one way is to alter the amino acid sequence(s) of them, producing analog insulins like Humalog, Novolog, NovoRapid and Apidra. Some of these (Humalog, Novolog) work by substituting or exchanging one or two amino acids at or near positions B-#28 & B-#29 so that insulin molecules will tend to remain separate instead of allowing them to clump together naturally into hexamersClinchem.org-Details Human Insulin Alterations for Humalog (Lispro), Novolog/NovoRapid (Aspart) & Lantus (Glargine). Apidra's substitutions are a bit different-at B-#3 and B-#29Prescribing Information-Apidra-Sanofi-Aventis. Using these types of alterations to force the insulin molecules to dissociate (remain apart, in the form of dimers and monomers, rather than their natural tendency to stay together), means they will be absorbed by the body faster. Another way of forcing the insulin hexamers to stay apart and speed their absorption is with a less than U100 strength of insulin. Diluting insulin into U40 strength forces them into dissociating (staying apart from each other, and becoming dimers and monomers), which means they are absorbedComparison of U100 and U40 Insulins-PubMedType 1 Diabetes Mellitus & Use of Flexible Insulin Regimens-Hirsch-American Family Physician-1999 better and more rapidlySubcutaneous Absorption of Insulin in Insulin-dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factors-PubMed-Danish medical Bulletin 1991. The factGerman Institute for Health Care Quality Study--English Translation that U40 insulin has a similar pharmacokinetic profile to analog insulin, has not been lost on the German Institute for Health Care Quality (government department). They proposed a cost-cutting move which would stop prescription coverage of the rapid-acting analogs for all newly-diagnosed Type 2 diabetics in Germany. This measure passed July 17, 2006Google Auto-Translated Page German Health Care Quality & Ecomony Institute Ruling, with rapid-acting analogs being covered only if they are similarly priced to non-analog insulin or if genuine intolerance can be medically demonstrated by the patient. The "Strength" section of the insulin page has more information and references regarding comparisons of the speed of U40 & U100 insulins. Slower-acting Other insulins, whether suspended or not, contain minute crystals of varying sizes which are deposited under the skin with the injection. Those with larger crystals, such as Ultralente, are absorbed slower than those with microfine ones, such as Semilente. Lente-type insulins are a "blend" of 30% faster-acting semilente crystals and 70% slower-acting Ultralente ones; this produces an intermediate-acting insulin. Mixed insulins are combined with a protamine suspension to keep them from being absorbed rapidly. Though it is not a suspended insulin, Lantus delays its absorption by not forming crystals until AFTER it has been injected and also via alterations made to the basic human insulin moleculeClinchem.org-Alterations of Human Insulin Producing Insulins Apart, Glargine & Lispro. Lantus's suspension is a special acidic preparation (pH 4.0) that reacts with the injection site forming micro-precipitates around the insulin crystals, which keeps them trapped for a while. Once the crystals make it to the bloodstream, they're absorbed as fast as any other insulin. Don't rub the injection site after injection or you can speed up absorption of Lantus and all other insulinsInsulin-Dependent Diabetes-Dr. Ragnar Hanas (Pages 12 & 13). Levemir uses an ordinary protamine suspension but has a genetically-engineered sticky "acyl side chain" that clings for a while to albumin (protein) molecules found in the bloodstream (and under the skin) that makes the Levemir molecule too big to enter/exit the bloodstream and therefore slows down its absorption, not only at the site but also in the bloodstream and at the target tissues. It is also possible to delay the absorption of an insulin by increasing its strength. U500 insulin, which is five times more concentrated than U100, has been available through both Lilly and Novo Nordisk (Note: Their similar product is U400 strength insulinUse of U500 Insulin in Patients With Extreme Insulin Resistance-Diabetes Care-ADA-2005) by special order for many yearsDiabetes Forecast-ADA,2006-Page 4. The insulin's main use is for people with extreme Insulin resistance, and is commercially available only in R/Neutral type. Though it is R/Neutral-type insulin, U400 & U500 insulins have a pharmacokinetic profile more like NPH insulin than U100 R/NeutralDiabetes-World Mailing List Web Site-Questions About Insulin. Since there are no additives such as suspensions to alter R/Neutral insulin's action, the strength of the insulin formula hinders its breakdown into dimers and monomers, thus making it much slower-absorbed than U100 and lesser strength insulinsFive Fold Increase of Insulin Concentration Delays the Absorption of Human Insulin Injections in Pigs-Diabetes Research & Clinical Practice-2000Use of U500 R Insulin by Continuous Insulin Infusion (Insulin Pump)in Patients With Type 2 Diabetes & Severe Insulin Resistance Endocrine Practice-2006. In cases of severe insulin resistance, using a much higher concentration of insulin appears to "negate" the effects of immune-related Insulin resistance. The studies at the link below shows that there was no difference regarding antibodies when these patients were transferred from Iletin II NPH at U100 strength to a form of Iletin II R at U500 strength. However, the stronger insulin reduced their insulin needs from 33-75%U500 Insulin in the Treatment of Antibody-Mediated Insulin Resistance-Annals of Internal Medicine-1981Enhanced Efficacy of U500 Insulin in the Treatment of Insulin Resistance Caused by Target Tissue Insensitivity-American Journal of Medicine-1984. Whether the insulin is slowed by the size of its crystals, by its suspension, by the strength of its concentration, or by amino acid alterations designed to delay its absorption--all of these are different mechanisms with the same goal in mind--to keep the insulin in hexamer form (thus preventing its fast absorption) as long as possible. Effect of origin People absorb r-DNA/GE/GM insulin at a faster rate than an otherwise identical pork or beef insulinDiabetes-World Mailing List Web Site-Questions About InsulinSubcutaneous Absorption of Insulin in Insulin-dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factor--PubMed/Danish Medical Bulletin 1991Comparison of the Safety and Effectiveness of Human and Bovine Long-acting Insulins-Diabetes Research-1989Diabetes Health-Faster Onset & Shorter Duration of GE Insulin in Humans, because it is an exact amino acid match to their ownComparing Activity Profiles of GE R(Neutral)/NPH(Isophane) With Different Fractions to Fixed-Fraction (70/30--30/70) Pork Mixed Insulin (Pork Mixtard 30)-Diabetes Care-ADA-1982Human, Porcine and Bovine Ultralente Insulin: Subcutaneous Administration in Normal Man-iabetic Medicine-1986. They absorb pork insulin a bit slower, because it is one amino acid away from theirsHuman & Porcine NPH (Isophane Insulins Unequally Effective in Diabetic Patients-Acta Diabetologica Latina-1984Comparison of Effects of Protamine-Bound NPH (Isophane) Porcine Insulin & NPH (Isophane) Human Insulin in T1 & T2 Diabetes-Deutsche Medizinische Wochenschrift (Translated into English)-1986. Slowest of all is beef insulin, as it is three amino acids away from a person's natural insulinComparison of NPH (Isophane) Human Insulin & NPH (Isophane) Bovine Insulin in Humans-Diabetes Care-ADA-1982Type I Diabetes and Insulin Therapy Nursing Clinics of North America-Hirsch-Farkas-Hirsch 1993Comparative Study of r-DNA NPH Insulin and Bovine NPH Insulin in Humans-Diabetes Care, 1982. It would be exactly opposite for dogs because their natural insulin is a perfect match to pork insulin, and one amino acid away from r-DNA/GE/GM insulin. Dogs would absorb pork insulin faster than an otherwise identical r-DNA/GE/GM human insulin. They would absorb beef insulin slower than either pork or r-DNA/GE/GM human insulin, as it is two amino acids away from a perfect match to their own. Origin, species, or source is very important as it directly affects the absorption, peak and duration of an insulinDiabetes Forecast-ADA, 2006-Page 3 Beef insulin, which is quite slow for human beingsInsulin Therapy-Overview, owing to the three amino acid difference between beef insulin and a human's own, would act more rapidly in cats, since it is the closest match we have to native feline insulin until r-DNA/GE/GM feline insulin comes along. Cats would absorb pork insulin slower than an otherwise identical beef insulin because of the 3 amino acid differences between them; they would absorb r-DNA/GE/GM human insulin slowest of all, because there are 4 amino acid differences in feline and human insulinBCP Veterinary Pharmacy-Bovine PZI InsulinComparison of 2 Ultralente Insulin Preparations With Protamine Zinc Insulin in Normal Cats-Americal Journal of Veterinary Research-1994. Effect of injection site Taking absorption outside the lab, many other factors come into play. A study done at the University of Minnesota showed that there is an 29-39% variation on the amount of insulin going into the bloodstream from one day to another Day To Day Variability Of Insulin. Absorption is faster when insulin is injected into limbs which are in motionDiabetes-World Mailing List Web Site-Questions About InsulinDiabetic Phenomena--WSAVA 2008 than in injection sites which are not--such as the back. Insulin also is absorbed faster via warmth--including the heat of summerDiabetes Mellitus Treatment-PetHealth101Diabetic Phenomena--WSAVA 2008. When blood flow is increased to the site of the insulin injection, absorption also increasesDiabetes-World Mailing List Web Site-Questions About Insulin. Both warmth and movement of the injection site increase increase blood flowType 1 Diabetes Mellitus & Use of Flexible Insulin Regimens-Hirsch-American Family Physician-1999Diabetes-World Mailing List Web Site-Questions About Insulin. Some diabetic cat caregivers report differing absorption rates with the same insulin depending on the injection site, the shot technique, and the needle length on the syringe. Absorption problems can occur possibly causing hypoglycemiaInsulin-Section 6.1-Kinetics or hyperglycemia if the insulin injection sites are not varied. The area needn't be very far from where the last shot was given--the distance of the width of 2 fingers will do fine as a measureJoslyn Diabetes Center-Tips for Injecting Insulin. When shots are given again & again into an area of skin, the tissue becomes thicker at that point; a fairly good analogy would be the calluses people get on hands and feet. The callus skin is thicker and harder; injection areas become similar to this too from repeated shots. This thicker, harder skin doesn't let the body absorb the injected insulin as well as thinner, non-hardened areasBD Diabetes-Injection Site Selection. Most of us dealing with pet diabetes vary the side we give the injections in--right side mornings and left side evenings, for example. This is another help in avoiding giving shots in the same areasBD Diabetes-FAQ's About Diabetic Dogs-Dr. Greco. Many people give insulin shots in the scruff of the pet's neck, which is now considered to be a less than optimum choice. The neck area provides poor insulin absorption, due to it not having many capillaries, veins. etc. (vascularization). Other sites suggested by Dr. Greco include the flank and armpitBetter Medicine E-Newsletter-June 2006. Intervet recommends giving injections from just back of the shoulder blades to just in front of the hipbone on either side, from 1 to 2 inches from the middle of the backVetsulin-Preparing Insulin & Giving Injection-Page 2. Levemir is too new to show any feline or canine data, but the manufacturer claimsNovo Nordisk Presentation--Less Variability that in their testing on humans they found much lower day-to-day variability Lower Day-to-Day Variability, even when shooting at different sites. They claim that this is because the Levemir "clinging" actionLevemir "Clinging" Action Movie takes place throughout the body and in the blood, and so is not dependent on injection site conditions. Depth of injection Subcutaneous (under the skin) injections are absorbed the slowest. Intramuscularly (into the muscle) given ones are absorbed much faster, but should not be given other than on the advice of a medical professionalDiabetic Phenomena-WSAVA 2008. Insulin dose The larger the dose of insulin, the longer it takes to be absorbedBernstein-The Law of Small Numbers Part 2 and the more duration it will haveDiabetic Phenomena-WSAVA 2008. Effect of body condition Cats and dogs who are dehydrated may have reduced insulin absorption rates; vomiting and diarrhea can cause both dehydration and hypoglycemia from themDiabetesNow-UK-Page 4. Dehydration can change the way subcutaneous insulin is absorbedAmerican College of Emergency Physicians-Pediatric Endorcrine Emergency Answer Sheet, causing either hyperglycemia or hypoglycemiaDiabetesNow-UK-Page 4. Those with diabetes are at risk for dehydration as it is triggered by hyperglycemiaHealthology.com-Diabetes/Dehydration. Other factors modulating insulin absorptionInsulin in the Hospital Setting, Ira B. Hirsch, U of Washington Medical Center include regional blood flow which is affected by exercise, rubbing or massage, and temperature. Effect of needle length Some caregivers report difference in insulin absorption with different length needles. BD DiabetesBDdiabetes.com-Using Short Needles explains that you should consult with your health care professional before using a short needle, and carefully monitor blood glucose when changing to a shorter needle. People have found their blood glucose not well-controlled when switching to the shorter needles; this also has been the case with some dogs. Switching back to a longer needle solved the problem. You should consider experimenting with the different length needles as insulin absorption may varyDiabetes Care-ADA Position Statement 2004. Further Reading *Absorption Kinetics of Regular, Isophane & Protamine Zinc Insulin in Normal Cats-Domestic Animal Endocrinology-1990 *Comparison of 2 Ultralente Insulin Preparations (Human & Beef/Pork)With Protamine Zinc (Beef/Pork) Insulin in Clinically Normal Cats-American Journal of Veterinary Research-1994 *Insulin Therapy in Cats With Diabetes Mellitus JAVMA-1983 Contains onset, peak & duration data for NPH/isophane & PZI insulins in cats. *Absorption Kinetics of Regular (Neutral) & Isophane (NPH)Insulin in the Normal Dog-Domestic Animal Endocrinology-1987 *Mechanism for Novolog (pdf) *Mechanism for Humalog (pdf) *A chart of the variations in amino acid sequence on the A and B chains of different species *Merck Veterinary Manual-Drug Absorption from Parenteral (injected) Delivery Sites References Category:InsulinsCategory:Action profileCategory:Terms